2,5-Disubstituted thiadiazoles as potent β-glucuronidase inhibitors; Synthesis, in vitro and in silico studies

Bioorg Chem. 2019 Oct:91:103126. doi: 10.1016/j.bioorg.2019.103126. Epub 2019 Jul 12.

Abstract

Twenty-five thiadiazole derivatives 1-25 were synthesized from methyl 4-methoxybenzoate via hydrazide and thio-hydrazide intermediates, and evaluated for their potential against β-glucuronidase enzyme. Most of the compounds including 1 (IC50 = 26.05 ± 0.60 μM), 2 (IC50 = 42.53 ± 0.80 μM), 4 (IC50 = 38.74 ± 0.70 μM), 5 (IC50 = 9.30 ± 0.29 μM), 6 (IC50 = 6.74 ± 0.26 μM), 7 (IC50 = 18.40 ± 0.66 μM), and 15 (IC50 = 18.10 ± 0.53 μM) exhibited superior activity potential than the standard d-saccharic acid-1,4-lactone (IC50 = 48.4 ± 1.25 μM). Molecular docking studies were conducted to correlate the in vitro results and to identify possible mode of interaction with enzyme active site.

Keywords: Docking study; SAR; Synthesis; Thiadiazoles; β-glucuronidase inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / metabolism
  • Glucuronidase / antagonists & inhibitors*
  • Glucuronidase / chemistry
  • Glucuronidase / metabolism
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Protein Binding
  • Structure-Activity Relationship
  • Thiadiazoles / chemistry*
  • Thiadiazoles / isolation & purification
  • Thiadiazoles / metabolism

Substances

  • Enzyme Inhibitors
  • Thiadiazoles
  • Glucuronidase